Neurotossicità iperammoniemia martinelli

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Information about Neurotossicità iperammoniemia martinelli
Health & Medicine

Published on February 4, 2014

Author: CentroMalattieRareFVG

Source: slideshare.net

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Disordini del ciclo dell'urea: la neurotossicità dell'iperammoniemia. Autore: Diego Martinelli, Unità Operativa Complessa Patologia Metabolica.

1 Disordini del ciclo dell’urea: la neurotossicità dell'iperammoniemia Diego Martinelli Unità Operativa Complessa Patologia Metabolica diego.martinelli@opbg.net Napoli 26 - 28 Novembre 2013

Pathogenetic Mechanisms of Hyperammonemia …in general the age of onset, duration and degree of hyperammonemia may predict prognosis…. ……….the underlying mechanisms of hyperammonemic encephalopathy are not completely understood……… Gropman A, Summar M, Leonard JV JIMD 2007;30:865-79 ...although several theories exist, it is not well understood how hyperammonemia disrupts brain function….. Gropman A MGM 2010;100:S20-S30

Clinical Manifestations NEONATAL • severe encephalopathy INFANCY – CHILDHOOD  ADULTHOOD • abnormal feeding with protein aversion • abnormal behaviour • recurrent vomiting • intermittent encephalopatic episodes • developmental delay • hepatitis like attacks • epilepsy • migraine • psychiatric symptoms • ataxia • stroke-like episodes

Hyperammonemia: possible scenarios • •  • • Genetic causes urea cycle defects organic acidurias -oxidation def. mitochondrial hyperinsulinism/hyperam monemia • • • • • Urea Cycle Defects Organic Acidurias -OX - mito Hi-Ha 0 500 1000 1500 Non-genetic causes THAN liver bypass/insufficiency asphyxia-shock-heart fail. infections intoxication Patient’s age • fetus • newborn • infant • child • adolescent • adult

The Urea Cycle urea glutamine alanine glutamate 6 enzymes 2 carriers NH4 0 normal Clay Chest 2007 2000 4000 6000 UCDs – liver failure 8000 10000 M

PROGNOSIS DEPENDS ON COMA DURATION Msall et al. NEJM 1984;310:1500-5 Picca et al. Pediatr Nephrol 2001;16:862-7 Good 2y 22.210.1 2210* pre-treatment Bad 2y 4711* *p<0.02 48.811.2 4911 7813

• PERI-INSULAR • FRONTAL • PARIETAL • OCCIPITAL ADC map ADC map • THALAMIC RESTRICTED DIFFUSION (unusual in UCDs) …suggesting that brain MRI may assist in determining prognosis & helping clinicians with subsequent treatment decisions

Pathogenetic Mechanisms of Hyperammonemia neuronal damage • • • • • • Glutamine induced cerebral edema Neurotransmitter perturbation Oxidative stress Neuroinflammation Energy failure Other……

Ammonia detoxification Periportal hepatocyte PORTAL blood NH4+ 300 M SYSTEMIC blood NH4+ 50 M Perivenous hepatocyte (astrocyte, muscle) ATP urea ADP glutamine Plasma gln during neonatal hyperammonemia Scriver 1995

Is glutamine synthesis the principal means of NH4 detoxification? glutamine

NH4+ 900 Propionic ac. Methylmalonic ac. p. Gln 420 Gln 1380 CSF NH4+ mol/L < 100 >100 p. Gln 397 386 NH4+ 470 560 970 Gln 640 229 369

The concentration changes of the nitrogen scavenger glutamine have to be interpreted in the light of NH4 levels. In contrast to other hyperammonemic syndromes, in PA plasma glutamine do not increase in hyperammonemia, whereas CSF glutamine concentrations are elevated. 2010

depletion of oxaloacetate (>methylcitrate production) reduced supply of succinyl-CoA  alfa-ketoglutarate  glutamate >  glutamine

Glutamine synthesis the principal means of NH4 detoxification? The osmotic action of glutamine CEREBRAL EDEMA NEURON ASTROCYTE SWELLING ASTROCYTE SWELLING NH4 NH4 Glutamate Glutamine GS Alzheimer type II astrocytosis Glutamine Alzheimer type II astrocytosis Glutamate

Glutamine induced cerebral edema hyperammonemia ↑ glutamine astrocyte swelling brain edema astrocyte dysfunction encephalopathy brain stem compression Citrullinemia 8 d NH3 2083 M hyperintensity basal ganglia, talami subcortical white matter cytotoxic edema Majoie 2004 OTC 2 d NH3 1000 M Multicystic lesions Yamanouchi 2002

Glutamine synthesis the principal means of NH4 detoxification? NEURON NH4 Gln Gase glutamine ROS NH4 Glu NH4 Gln regenerated in mitochondria ASTROCYTE Gln Gase NH4 Gln Glu GS NH4 Glu ROS MTP ROS astroglyal dysfunction ENCEPHALOPATHY Albrecht & Norenberg Hepatol 2006

Pathogenetic Mechanisms of Hyperammonemia neuronal damage • • • • • • Glutamine induced cerebral edema Neurotransmitter perturbation Oxidative stress Neuroinflammation Energy failure Other……

Transmitters and Receptors • Increased aromatic amino acids uptake precursors of neurotransmitters • Glutamatergic excitotoxicity • Impairement of cholinergic transmission • Increased serotoninergic transmission • False transmitters compete with normal transmitters  Tyramine  Octopamine  Phenylethanolamine

glutamate NMDA Ca++ ROS ATP  NOS ASTROCYTE Ca MTP Na+ ATP  ++ Na+ Calcineurin Calmodulin NO POST-SYNAPTIC NEURON glutamate NH4 GS Gln Na+

Pathogenetic Mechanisms of Hyperammonemia neuronal damage • • • • • • Glutamine induced cerebral edema Neurotransmitter perturbation Oxidative stress Neuroinflammation Energy failure Other……

The role of oxidative stress glutamate NEURON NMDA Ca++ Gln Gase Na+ ROS NH4 Glu ROS Gln ATP  Ca++ Na+ ASTROCYTE ATP  Gln Gase NH4 Glu iNOS ROS ASTROCYTE MTP Calcineurin Calmodulin NO POST-SYNAPTIC NEURON NH4 Glu Gln glutamate GS NH4 MPT NH4 ROS NEURONAL astroglyal dysfunction ENCEPHALOPATHY GS Gln Na+

Pathogenetic Mechanisms of Hyperammonemia neuronal damage • • • • • • Glutamine induced cerebral edema Neurotransmitter perturbation Oxidative stress Neuroinflammation Energy failure Other……

Hepatic encephalopathy: role of inflammation HYPOTHERMIA N-ACETYL-CYSTEINE IBUPROFEN NEURON NEUROINFLAMMATION TNF- IL-6 IL-1 TNF- IL-6 IL-1 MICROGLIAL ACTIVATION MICROGLIAL ACTIVATION BBB INFECTION – INFLAMMATION blood capillary NH4 – LACTATE

Pathogenetic Mechanisms of Hyperammonemia neuronal damage • • • • • • Glutamine induced cerebral edema Neurotransmitter perturbation Oxidative stress Neuroinflammation Energy failure Other……

The role of energy failure NH4+ exposure generates secondary Cr deficiency in brain cell cultures Braissant 2010 • altered oxidative phosphorylation • cessation of ATP synthesis • production of ROS and cell death

Pathogenesis of brain damage in HA: others Astrocyte swelling can cause a secondary release of Glu into the intercellular space KGM neurotoxic ? ** * ↑↑ «Trojan horse» hypothesis SNAT5 Modified from Braissant; J Inherit Metab Dis (2013) 36:595–612 *KMG : α-ketoglutaramate; AKGM are increased in UCDs ROS ↑↑ MPT open ↓↓ SNAT5. Trapping GLn Altered Neurotrasnsmitter system **Imp:, brain NO metabolism is affected in a number of ways by NH4 + exposure. Effects vary depending on whether the exposure is acute or chronic, on brain cell type, and whether Arg supply is normal or decreased Braissant; J Inherit Metab Dis (2013) 36:595–612;Albrecht; Hepatolgoy . 2006 Oct;44(4):788-94; Halámková; Talanta. 2012 Oct 15;100:7-11; Vergara F et al; Science 1974;183:81-83; P. Desjardins et al. / Neurochemistry International 60 (2012) 690–696

Pathogenesis underlying brain dysfunction. Acute and chronic hyperammonemia Conclusions • How HA can lead to severe consequences in the central nervous system (CNS) remains unclear. • The rise in ammonia levels, the elevations of glutamine, and the effect of glutamine on the brain are proposed to account for the different effects of acute (vs chronic) hyperammonemia on the brain. • In acute hyperammonemia the excessive NMDA receptors activation could be inducing neuronal death • In chronic hyperammonemia the impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors could be inducing cognitive impairment. • N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors are fundamental for learning because they are the major modulators of the long-term potentiation, the electrophysiologic mechanism for learning. Braissant; J Inherit Metab Dis (2013) 36:595–612;Albrecht; Hepatolgoy . 2006 Oct;44(4):788-94; Halámková; Talanta. 2012 Oct 15;100:7-11; Vergara F et al; Science 1974;183:81-83; P. Desjardins et al. / Neurochemistry International 60 (2012) 690–696; Cauli O et al Metab Brain Disease ; 2009 Mar;24(1):69-80; Alison S. Et al ; Chest Chest 2007;132;1368-1378

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